tbuckley/cabot-search huggingface dataset:
Abstract 2668: Targeting of ERK and HDAC in the treatment of uveal melanoma
Authors: Elgilda Musi, Kim-Hien Dao, Chris Hindley, Gary K. Schwartz
Journal: Cancer Research (2022)

Abstract Uveal melanoma is one of the most common intraocular malignancies of the adult eye. GNAQ/GNA11 genetic alterations are present in 85% of cases resulting in activation of the MAPK pathway. Single agent approaches targeting the MAPK pathway and histone deacetylases (HDACs) have shown very modest activity in uveal melanoma. We hypothesize that a combination strategy may be an effective, novel therapeutic approach in uveal melanoma. We examined the activity of ASTX029, a novel dual-mechanism ERK inhibitor, which inhibits both the catalytic activity of ERK and its phosphorylation by MEK, and belinostat, a pan-HDAC inhibitor, in one GNAQQ209L- (92.1) and GNAQQ209P- (OMM1.3) and two GNA11Q209L-mutant (MP41, OMM1) uveal melanoma cell lines. The uveal melanoma cell lines were sensitive to ASTX029 with IC50 values between 50 to 100nM and to belinostat with IC50 values between 100 to 250nM. Combination index analysis of ASTX029 and belinostat by the Chou-Talalay method indicated synergism, with CI values ranging from 0.34 to 0.97. We explored other drug candidates for combinatorial approaches including the BCL-2 inhibitor navitoclax, but no combination effect was observed. After 48h of combination treatment with ASTX029 and belinostat, we examined the biochemical effects by western blot which demonstrated a sustained decrease in levels of p-ERK with the combination treatment. Western blot analysis confirmed reduction of downstream markers of MAPK pathway activity including cell cycle markers p-RB (780), cyclin D1 and c-myc with combination treatment. Apoptosis was evident from an increase in the subG1 population by flow cytometry analysis, which correlated with BIM induction and PARP cleavage on western blot. We also observed increased surface expression of immunological markers HLA-A, B, C (MHC Class 1), PD-L1, gp100 and MART-1. These results support that a combination strategy targeting ERK and HDAC in uveal melanoma should be investigated further. Citation Format: Elgilda Musi, Kim-Hien Dao, Chris Hindley, Gary K. Schwartz. Targeting of ERK and HDAC in the treatment of uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2668.
Lessons That Are Never Forgotten—The <i>Unknown</i> Session
Authors: William D. James
Journal: JAMA Dermatology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Abstract 1104: Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines
Authors: Alejandra Agredo, Arpita Pal, Nadia Lanman, Jihye Son, Andrea L. Kasinski
Journal: Cancer Research (2022)

Abstract Although important advancements have been achieved in the treatment of cancer, lung cancer is still the leading cause of cancer-related deaths in both men and women, with an estimated 1.6 million deaths each year. Non-small cell lung cancer (NSCLC), which makes up ~85% of lung cancer cases, is mainly treated with radiotherapy, chemotherapies, and targeted agents. Epidermal growth factor receptor (EGFR) is commonly mutated in NSCLC patients and leads to increased proliferation and cell survival. The standard-of-care treatment for patients harboring activating mutations in EGFR is treatment with tyrosine kinase inhibitors (TKI), such as erlotinib. While tumors initially respond to TKIs, after 1-2 years most of the patients develop resistance. In ~60% of patients, TKI resistance is the results of a secondary mutation in EGFR, leading to sustained receptor activation. Whereas, in the remaining 20%, tumors turn on bypass tracks-signals to overcome inhibition of the EGFR pathway. However, in 15-20% of the cases the mechanisms underlying resistance are unknown. Hence, there is a need to identify additional mechanisms involved in TKIs resistance. Our laboratory performed a genome-wide CRISPR Cas9 knock-out screen to identify genes that when knocked-out would drive erlotinib resistance. Fold enrichment analysis of sgRNAs, identified the protein coding gene SUV420H2 as a top candidate. SUV420H2 is a histone methyltransferase that trimethylates H4K20 (H4K20me3), enabling the establishment of constitutive and facultative heterochromatin. The process by which SUV420H2 is reduced in tumors is unknown, yet data from human samples suggests that SUV420H2 is globally downregulated in NSCLC. Additionally, loss of H4K20me3, the modification made by SUV420H2, in preneoplasia influences prognosis of NSCLC, indicating that loss of SUV420H2 function is a crucial mechanism in carcinogenesis. SUV420H2 expression has historically been associated with generating constitutive heterochromatin. However, more recently SUV420H2 was found to silence euchromatin regions. Our recent data suggests that SUV420H2 leads to reduced transcription of the oncogene MET by silencing the oncogenic long non-coding RNA LINC01510 upstream of MET. These findings led us to hypothesize that loss of SUV420H2 leads to erlotinib resistance through to upregulation of oncogenes including MET. Moreover, we aim to identify genes that are dynamically regulated by SUV420H2 using chromatin immunoprecipitation in NSCLC cell lines to further understand SUV420H2-mediated gene regulation and its role in TKIs resistance. Citation Format: Alejandra Agredo, Arpita Pal, Nadia Lanman, Jihye Son, Andrea L. Kasinski. Loss of SUV420H2 drives EGFR inhibitor resistance in EGFR mutant NSCLC cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1104.
Abstract 4004: Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes
Authors: Anna Köferle, Andreas Schlattl, Alexandra Hörmann, Fiona Spreitzer, Alexandra Popa, Venu Thatikonda, Teresa Puchner, Verena Supper, Madhwesh C. Ravichandran, Sarah Oberndorfer, Corinna Wieshofer, Maja Corcokovic, Christoph Reiser, Simon Wöhrle, Johannes Popow, Mark Pearson, Barbara Mair, Ralph A. Neumüller
Journal: Cancer Research (2022)

Abstract Genetic networks are characterized by extensive buffering. During tumor evolution, disruption of these functional redundancies can create de novo vulnerabilities that are specific to cancer cells. In this regard, paralog genes are of particular interest, as the loss of one paralog gene can render tumor cells dependent on a remaining paralog. To systematically identify cancer-relevant paralog dependencies, we searched for candidate dependencies using CRISPR screens and publicly available loss-of-function datasets. Our analysis revealed &amp;gt;2,000 potential candidate dependencies, several of which were subsequently experimentally validated. We provide evidence that DNAJC15-DNAJC19, FAM50A-FAM50B and RPP25-RPP25L are novel cancer relevant paralog dependencies. Importantly, our analysis also revealed unexpected redundancies between sex chromosome genes. We show that chrX- and chrY- encoded paralogs, as exemplified by ZFX-ZFY, DDX3X-DDX3Y and EIF1AX-EIF1AY, are functionally linked so that tumor cell lines from male patients with Y-chromosome loss become exquisitely dependent on the chrX-encoded gene. We therefore propose genetic redundancies between chrX- and chrY- encoded paralogs as a general therapeutic strategy for human tumors that have lost the Y-chromosome. Citation Format: Anna Köferle, Andreas Schlattl, Alexandra Hörmann, Fiona Spreitzer, Alexandra Popa, Venu Thatikonda, Teresa Puchner, Verena Supper, Madhwesh C. Ravichandran, Sarah Oberndorfer, Corinna Wieshofer, Maja Corcokovic, Christoph Reiser, Simon Wöhrle, Johannes Popow, Mark Pearson, Barbara Mair, Ralph A. Neumüller. Interrogation of cancer gene dependencies reveals novel paralog interactions of autosome and sex chromosome encoded genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4004.
Abstract 5923: Rapid spectroscopic liquid biopsy for the early detection of brain tumors
Authors: Alexandra Sala, Ashton G. Theakstone, Paul M. Brennan, Michael D. Jenkinson, Samantha J. Mills, Khaja Syed, Christopher Rinaldi, Yun Xu, Royston Goodacre, Holly J. Butler, David S. Palmer, Benjamin R. Smith, Matthew J. Baker
Journal: Cancer Research (2022)

Abstract To support the early detection and diagnosis of brain tumors we have developed a rapid, cost-effective and easy to use spectroscopic liquid biopsy based on the absorbance of infrared radiation. We have previously reported highly sensitive results of our approach which can discriminate patients with a recent brain tumor diagnosis and asymptomatic controls. Other liquid biopsy approaches (e.g., based on tumor genetic material) report a lower classification accuracy for early-stage tumors. In this manuscript we present an investigation into the link between brain tumor volume and liquid biopsy test performance. In a cohort of 177 patients (90 patients with high-grade glioma (glioblastoma (GBM) or anaplastic astrocytoma), or low-grade glioma (astrocytoma, oligo-astrocytoma and oligodendroglioma)) tumor volumes were calculated from magnetic resonance imaging (MRI) investigations and patients were split into two groups depending on MRI parameters (T1 with contrast enhancement or T2/FLAIR (fluid-attenuated inversion recovery)). Using attenuated total reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy coupled with supervised learning methods and machine learning algorithms, 90 tumor patients were stratified against 87 control patients who displayed no symptomatic indications of cancer, and were classified as either glioma or non-glioma. Sensitivities, specificities and balanced accuracies were all greater than 88%, the area under the curve (AUC) was 0.98, and cancer patients with tumor volumes as small as 0.2 cm3 were correctly identified. Our spectroscopic liquid biopsy approach can identify gliomas that are both small and low-grade showing great promise for deployment of this technique for early detection and diagnosis. Citation Format: Alexandra Sala, Ashton G. Theakstone, Paul M. Brennan, Michael D. Jenkinson, Samantha J. Mills, Khaja Syed, Christopher Rinaldi, Yun Xu, Royston Goodacre, Holly J. Butler, David S. Palmer, Benjamin R. Smith, Matthew J. Baker. Rapid spectroscopic liquid biopsy for the early detection of brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5923.
Abstract 927: Developing new mouse models of metastatic lung cancer
Authors: Julie Wells, Richard Maser, Ashley Tucker, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult
Journal: Cancer Research (2022)

Abstract INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and greater than 75% of human lung cancer deaths can be attributed to metastasis. Metastatic disease in most existing mouse models of pulmonary adenocarcinoma is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of mouse models for basic and pre-clinical research aimed at identifying effective treatments of metastatic disease. METHODS AND RESULTS: We have developed new mouse models of pulmonary adenocarcinoma in which we added mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway to a mouse model of Kras-driven pulmonary adenocarcinoma. For both models, we induced tumorigenesis by conditionally expressing an oncogenic allele of Kras (KrasG12D), deleting of both alleles of Trp53 and deleting one allele of Dicer1 in one cell population then expressing truncated Dicer1 in a different cell population. In the absence of Dicer1 truncation, mice expressing KrasG12D and deleting Trp53 in Club cells have a reported median survival of 28.6 weeks after tumor induction. When we also deleted one allele of Dicer1 in Club cells and truncated Dicer1 in alveolar type II cells of these mice, they exhibited respiratory distress and began dying 12.1 weeks after tumor induction. In our initial pilot study, all animals (12/12) developed pulmonary adenocarcinoma and 30% (3/10) had lymph node metastasis. We did not observe accelerated tumorigenesis, however, when we switched cell types, inducing tumorigenesis in alveolar type II cells and truncating Dicer1 in Club cells, or when induced tumorigenesis and truncating Dicer1 within the same cell populations. CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated a new mouse model that rapidly develops pulmonary adenocarcinomas and metastatic disease. Our findings support our hypothesis that tumorigenesis and metastasis are influenced by miRNA regulated communication between different cell types. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer. Citation Format: Julie Wells, Richard Maser, Ashley Tucker, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 927.
Abstract 6012: Antitumor effect of natural killer cells on breast cancer cells in murine model
Authors: Chaok Yim, Jun Woo Lee, Jin-Hee Kim
Journal: Cancer Research (2022)

Abstract Natural killer (NK) cells are play pivotal functions in the tumor microenvironment of cancer immune surveillance. The killing ability of NK cells is expected to contribute to death of cancer cell. To prove NK cells as a cell therapy, we frist manufactured NK cells from the peripheral blood of healthy donor who received informed consent in a GMP facility. And we verifed the killing ability of the NK cells by decreasing the size of the tumor in NOG mice inoculated with SKBR3, HER2-positive breast-cancer cell, into mammary fat pad (orthotopic models). In this study, sudden death of mice was not found even when 20 millions NK cells were injected into a NOG female with intravenous injection. Moreover, it was confirmed that the size of the tumor was significantly reduced after NK cell injection. It is necessary to study co-administration with a targeted therapy such as rastuzumab and pertuzumab, and NK cells as a cell therapy will help reduce the size of the tumor. In the future, additional research is needed on the combined administration of targeted therapeutics and NK cells. Citation Format: Chaok Yim, Jun Woo Lee, Jin-Hee Kim. Antitumor effect of natural killer cells on breast cancer cells in murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6012.
Abstract 1363: Preclinical development of bispecific CAR-T cells for canine B cell malignancies
Authors: Matthew J. Atherton, Antonia Rotolo, Nicola J. Mason
Journal: Cancer Research (2022)

Abstract Chimeric antigen receptor (CAR)-T cells targeting CD19 have revolutionized the treatment of B cell malignancies in people. However, post-treatment loss of CD19 has emerged as an adaptive mechanism of resistance. Pet dogs that develop tumors spontaneously in an immune competent setting represent a compelling parallel population of patients to study next generation cancer immunotherapies. Comparative trials at the University of Pennsylvania are investigating the activity of canine CAR-T cells targeting either CD19 or CD20 in canine B cell lymphoma patients and have revealed a favorable safety profile with early signs of anti-tumor activity. Aligned with experiences in human trials, expansion of CD20-negative B cells has been observed in dogs treated with anti-CD20 CAR-T cells. Bispecific CAR-T cells that simultaneously target two antigens to mitigate antigen escape have encouraging efficacy profiles in human patients. Thus, we designed a dual-targeting CAR specific for canine B cell antigens. A second-generation canine CAR construct targeting both CD19 and CD20 with a 28z signaling domain was cloned into the MSGV1 backbone. Chimeric retrovirus encoding RD114 and VSV-G envelope proteins and the CAR construct was made using GP2-293 cells. Jurkat NFAT-GFP reporter cells and primary T cells from dogs diagnosed with high grade B cell lymphoma were retrovirally transduced with bispecific CARs. Antigen specific reactivity was assessed against cell lines with variable CD19 and CD20 expression patterns. The CD19-CD20 CAR was efficiently transduced, with stable expression in both Jurkat and primary canine T cells. Jurkat reporters revealed dual-specific CAR signaling after co-culture with CD19+ and/or CD20+ target cells. Primary canine CAR-T cells expanded in vitro and exhibited CAR-specific proliferation and cytotoxicity against CD19+ CD20+ target cells. Preclinical manufacture of functional, bispecific anti-CD19 anti-CD20 canine CAR-T cells is feasible. A clinical trial recruiting dogs diagnosed with B cell cancer will assess safety and efficacy of this approach in vivo, with the aim of establishing the dog as a compelling model to appraise the ability of bispecific CAR-T cells to overcome therapeutic failures secondary to antigen loss. Citation Format: Matthew J. Atherton, Antonia Rotolo, Nicola J. Mason. Preclinical development of bispecific CAR-T cells for canine B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1363.
Abstract 3236: CDK7 Expression is a biomarker of resistance to olaparib
Authors: Gilad Silberberg, Bandana Vishwakarma, Paul Heverly, Marianna Zipeto, David DeOrnellis, Michael Ritchie
Journal: Cancer Research (2022)

Abstract The overall survival of patients diagnosed with Ovarian Cancer remains low. The current initial treatment regimen for patients with newly diagnosed advanced ovarian cancer includes the use of paclitaxel and carboplatin in combination with surgical cytoreduction. Remission is often achieved, but 80% of patients will have a recurrence within 3 years of remission. Recent treatment advances include the use of poly(ADP)-ribose polymerase (PARP) inhibitors for recurrent tumors with associated BRCA mutations. While maintenance treatment with PARP inhibitors results in remission for a significant number of patients, acquired resistance to therapy has been observed. In this study, we evaluated biomarkers associated with resistance to the PARP inhibitor Olaparib in a cohort of platinum pretreated Ovarian Cancer tumors. We identified Cyclin H and CDK7 expression, among others, as biomarkers associated with resistance to Olaparib. Further prospective analyses confirmed CDK7 expression as a biomarker of resistance to Olaparib in NSCLC. Citation Format: Gilad Silberberg, Bandana Vishwakarma, Paul Heverly, Marianna Zipeto, David DeOrnellis, Michael Ritchie. CDK7 Expression is a biomarker of resistance to olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3236.
Abstract 6200: MANGO: pipeline for identifying genomic translocations with key biological significance in inflammatory breast cancer
Authors: Carlos S. Morales-Rivera, Emilia R. Driscoll, Esther A. Peterson-Peguero
Journal: Cancer Research (2022)

Abstract Genomic instability in cancer is essential for aberrant gene expression and translocation events that potentiate oncogenesis. Thus gene fusions, nonsense mutations and gene deregulation are key contributors to oncogenic phenotypes. Certain genomic translocations have been linked to cancer subtypes, such BCR—ABL1 for chronic myeloid leukemia (CML) serving as potential onco-biomarkers. Inflammatory breast cancer (IBC) is the rarest and most lethal subtype of breast cancer with a 5-year survival rate below 50%. Ethnic disparities for breast cancer exist; negative estrogen (ER) and progesterone (PR) hormone receptor status is more frequent in Hispanic and African American women. In addition, inflammatory breast cancer lacks defined molecular markers limiting its early onset detection which leads to poorer overall prognosis. Thus, we hypothesized that profiling IBC translocations, including its subtypes, show valuable insights to better understand this complex disease. We developed MANGO, a pipeline that leverages STAR, STAR-Fusion, FusionInspector, and Trinity to identify, visualize and assemble gene fusions from IBC sequencing data. Using the SUM149PT cell line as a model for IBC, we identified and experimentally validated a model fusion gene ZDHHC5—EPB41L5. Fusion unaware sequence assemblies cross-validated the fusion and its multiple splice sites, one of which encodes a fusion peptide. Differential gene expression between SUM149PT and SUM190PT, an IBC cell line without evidence for the identified translocation, showed loss of expression of ZDHHC5 but no change in EPB41L5, suggesting the latter retained its expression in its new genomic localization. Furthermore, in-silico functional predictions for experimental results reveals an in-frame fusion peptide with transmembrane signals in EPB41L5. Genomic translocation mapping reveals triple-negative IBC diverges from traditional breast cancer translocation patterns. In short, MANGO serves as a powerful tool to identify biologically significant translocations involved in IBC and other cancer classifications. Citation Format: Carlos S. Morales-Rivera, Emilia R. Driscoll, Esther A. Peterson-Peguero. MANGO: pipeline for identifying genomic translocations with key biological significance in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6200.